Bilastine, CAS 202189-78-4, C₂₈H₃₇N₃O₃, relative molecular mass 463.6 g/mol, is a zwitterionic H₁ receptor antagonist supplied as a white to almost white crystalline powder for tablet, capsule, granule, and injectable dosage-form development. The API is the free amphoteric molecule; it is not a hydrochloride or maleate salt. Its human H₁ receptor inhibition constant K_i is reported at 44.5 nM. The material is controlled for residual solvents under ICH Q3C, elemental impurities under ICH Q3D, and related substances under ICH Q3A; release assay by reversed-phase HPLC is typically controlled at 98.0–102.0% on the dried basis, with total related substances not more than 0.5%. Karl Fischer water content per Ph. Eur. 2.5.12 is grade-specific but is normally held below 0.5% for oral solid-dose grades. Injectable-grade material is additionally tested for bacterial endotoxins per Ph. Eur. 2.6.14 at a limit of not more than 0.5 EU/mg. Route-specific product models are differentiated by particle size, endotoxin load, and residual solvent profile rather than by molecular identity.

How Does Air-Jet Milling Influence Powder Flow and Content Uniformity in Bilastine Oral Solid-Dose Forms?

Oral solid-dose grades of bilastine are commonly produced by spiral jet milling or pin milling to reduce primary particle size and increase specific surface area. Particle size distribution is determined by laser diffraction per ISO 13320-1:2020. For immediate-release tablet and capsule formulations, a D₉₀ of ≤20 µm and a D₅₀ of ≤5 µm are routinely specified because dissolution rate in the physiological pH range becomes surface-area controlled according to the Noyes-Whitney equation. Milled bilastine is cohesive; powder flow measurements per Ph. Eur. 2.9.36 often show Carr index values above 25%, and bulk density measured per Ph. Eur. 2.9.34 may fall below 0.40 g/mL. These values indicate that direct compression of the unmilled or air-jet-milled API without excipients is not an acceptable manufacturing route. On a rotary tablet press with a forced feeder, die filling and content uniformity at a target of ±5% of label claim require either roller compaction dry granulation or wet granulation with densified API. When 20 mg bilastine tablets are manufactured by direct compression using a blend of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate, the milled API is first pre-blended with a portion of the diluent for 10–15 min in a bin blender at 10–15 rpm to ensure deagglomeration before the remaining excipients are added.

Granulation-grade bilastine is densified to improve flow and reduce segregation. In a high-shear granulator with a 10 L bowl, wet granulation with purified water or aqueous hypromellose binder at an impeller speed of 150–300 rpm and a chopper speed of 1,500–3,000 rpm produces granules with bulk density between 0.45 g/mL and 0.60 g/mL. Fluid-bed drying at an inlet air temperature of 60–70 °C to a loss on drying of 1.0–2.0% reduces sticking and picking during subsequent compression. The dried granules are passed through a 1.0 mm screen and blended with extra-granular disintegrant and lubricant. If magnesium stearate is used, blending time is limited to 3–5 min at 10–15 rpm to avoid overlubrication, which can retard dissolution by forming a hydrophobic film on granule surfaces. Tablet hardness is typically controlled between 80 N and 150 N and disintegration tested per Ph. Eur. 2.9.1 with a limit of NMT 15 min in purified water at 37 °C, although the specific limit depends on the intended dissolution profile.

Injection Grade Solubilisation Limits and Endotoxin Control

Bilastine injectable-grade API is chemically identical to the oral grade but is released under low-bioburden and low-endotoxin conditions. In the pH range 4.0–8.0, the amphoteric molecule exists predominantly as a zwitterion with limited aqueous solubility; this restricts the preparation of isotonic solutions at neutral pH. Parenteral development therefore requires pH adjustment to 4.0–5.0 with citrate or acetate buffer, or the use of a co-solvent system based on propylene glycol, polyethylene glycol, or a cyclodextrin derivative, to reach a working concentration of 2.5–5.0 mg/mL. Published data for these specific vehicle combinations remains limited, and solubility must be measured for each prototype using a validated HPLC assay. The bulk solution is sterilised by filtration through a 0.22 µm polyethersulfone or polyvinylidene fluoride membrane per Ph. Eur. 5.1.1, followed by aseptic filling. Sub-visible particulate matter is controlled per Ph. Eur. 2.9.19 or USP <788>; for 10 mL parenterals, the container meets the limit of not more than 6,000 particles per container at ≥10 µm and not more than 600 particles per container at ≥25 µm for single-dose containers. Bacterial endotoxin testing uses a kinetic chromogenic LAL method per Ph. Eur. 2.6.14; the injectable-grade API limit of 0.5 EU/mg must be confirmed because the API is non-sterile and cannot be terminally sterilised without stability data.

Container closure compatibility is evaluated with type I borosilicate glass vials and chlorobutyl rubber stoppers. Because bilastine has limited aqueous solubility, any pH adjustment using hydrochloric acid or sodium hydroxide can increase chloride or sodium concentration; osmolality is adjusted to 270–328 mOsm/kg with mannitol or sodium chloride. The formulation is sparged with nitrogen if oxygen-sensitive; however, published data regarding bilastine oxidation in solution is limited and oxygen uptake should be measured during forced degradation studies.

If Polymorphic Transitions Occur During Wet Granulation or Tablet Compression

Bilastine solid-state characterisation is performed by X-ray powder diffraction per Ph. Eur. 2.9.33 and differential scanning calorimetry per Ph. Eur. 2.2.34. XRPD analysis is used to confirm that the crystalline form remains unchanged after granulation. Differential scanning calorimetry at a heating rate of 10 K/min under nitrogen records the characteristic melting endotherm. If a polymorphic transition occurs during wet granulation or compression, the X-ray diffractogram and dissolution behaviour are altered; therefore, the granulation-drying temperature is limited to ≤70 °C to minimise the risk of solvent-mediated transformation. Compression force is also monitored; excessive main compression above 25 kN for a 9 mm round bevel-edge tablet can increase tablet density and reduce disintegration time unless disintegrant is added at 2–5% w/w.

What Differentiates Bilastine from Cetirizine, Levocetirizine, and Fexofenadine in P-glycoprotein Substrate Status?

Bilastine is a substrate of the efflux transporter P-glycoprotein; this property is central to its low central nervous system H₁ receptor occupancy at therapeutic doses. Fexofenadine shares this efflux-driven peripheral selectivity, whereas cetirizine and levocetirizine are not considered strong P-gp substrates and cross the blood-brain barrier to a greater extent. In radioligand displacement assays, bilastine has negligible affinity for muscarinic M₁, α₁-adrenergic, 5-HT₂, and H₂ receptors at concentrations up to 10 µM. The therapeutic dose is 20 mg once daily for adults and adolescents; time to maximum plasma concentration is approximately 1.5 h, elimination half-life is 14.5 h, and plasma protein binding is 84–90%. The oral bioavailability is approximately 60%. Unlike older first-generation antihistamines, bilastine does not carry the same muscarinic receptor occupancy burden; however, it is not indicated for acute anaphylaxis or as an injectable rescue therapy. Comparative dosing and pharmacokinetic parameters are controlled by the finished-product label in each regulatory region.

Dissolution testing for bilastine tablets is performed per Ph. Eur. 2.9.3 or USP <711> Apparatus II at 50 rpm in 900 mL of 0.1 M hydrochloric acid or pH 4.5 acetate buffer. The intrinsic dissolution rate is pH-dependent; at pH 1.2, release is rapid, whereas at pH 6.8 phosphate buffer, solubility-limited dissolution slows release. This pH dependence must be considered when differentiating bioequivalent prototypes. If a disintegration method is used, the limit of NMT 15 min in purified water at 37 °C is only a preliminary test and does not replace dissolution.

Elemental impurity risk assessment follows ICH Q3D and the product is tested for Class 1 and Class 2A metals. Where palladium catalysis is used in the route, palladium is controlled by inductively coupled plasma mass spectrometry at a limit typically not more than 10 µg/g, with the final limit determined by the intended route and permitted daily exposure. Residual solvents are measured by headspace gas chromatography; ethanol, ethyl acetate, and isopropanol are typical process solvents controlled to ICH Q3C concentration limits. Any use of methyl tert-butyl ether or dichloromethane in the final recrystallisation is excluded for injectable-grade material because of the stricter options for parenteral products.

For tablet and capsule formulations, oral-grade micronized bilastine is used to enhance dissolution and content uniformity. Granules for powder-in-bottle or sachet presentations use a densified coarse grade to reduce dusting and improve volumetric dosing. Injectable formulations use the low-endotoxin grade and require additional solubility enhancement. In each case, the API specification must reflect the intended route: oral grades are tested for microbial limits per Ph. Eur. 2.6.12; injectable grades are tested for endotoxin and sub-visible particulates only after formulation; the API itself is not sterile. If a manufacturer claims sterile bilastine API, sterility data per Ph. Eur. 2.6.1 or USP <71> must be provided, because non-sterile API cannot be treated as sterile by simple filtration.